FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2070542281> ?p ?o ?g. }

• W2070542281 endingPage "2010" @default.
• W2070542281 startingPage "2002" @default.
• W2070542281 abstract "Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which there is a progressive loss of motor neurons and their connections to muscle, leading to paralysis. In order to maintain muscle connections in a rat model of familial ALS (FALS), we performed intramuscular transplantation with human mesenchymal stem cells (hMSCs) used as “Trojan horses” to deliver growth factors to the terminals of motor neurons and to the skeletal muscles. hMSCs engineered to secrete glial cell line–derived neurotrophic factor (hMSC-GDNF) were transplanted bilaterally into three muscle groups. The cells survived within the muscle, released GDNF, and significantly increased the number of neuromuscular connections and motor neuron cell bodies in the spinal cord at mid-stages of the disease. Further, intramuscular transplantation with hMSC-GDNF was found to ameliorate motor neuron loss within the spinal cord where it connects with the limb muscles receiving transplants. While disease onset was similar in all the animals, hMSC-GDNF significantly delayed disease progression, increasing overall lifespan by up to 28 days, which is one of the largest effects on survival noted for this rat model of FALS. This preclinical data provides a novel and practical approach toward ex vivo gene therapy for ALS. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which there is a progressive loss of motor neurons and their connections to muscle, leading to paralysis. In order to maintain muscle connections in a rat model of familial ALS (FALS), we performed intramuscular transplantation with human mesenchymal stem cells (hMSCs) used as “Trojan horses” to deliver growth factors to the terminals of motor neurons and to the skeletal muscles. hMSCs engineered to secrete glial cell line–derived neurotrophic factor (hMSC-GDNF) were transplanted bilaterally into three muscle groups. The cells survived within the muscle, released GDNF, and significantly increased the number of neuromuscular connections and motor neuron cell bodies in the spinal cord at mid-stages of the disease. Further, intramuscular transplantation with hMSC-GDNF was found to ameliorate motor neuron loss within the spinal cord where it connects with the limb muscles receiving transplants. While disease onset was similar in all the animals, hMSC-GDNF significantly delayed disease progression, increasing overall lifespan by up to 28 days, which is one of the largest effects on survival noted for this rat model of FALS. This preclinical data provides a novel and practical approach toward ex vivo gene therapy for ALS. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor dysfunction that leads to eventual paralysis.1Brown Jr, RH Amyotrophic lateral sclerosis: recent insights from genetics and transgenic mice.Cell. 1995; 80: 687-692Abstract Full Text PDF PubMed Scopus (333) Google Scholar,2Cleveland DW Rothstein JD From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS.Nat Rev Neurosci. 2001; 2: 806-819Crossref PubMed Scopus (1188) Google Scholar The majority of ALS cases are of a sporadic nature, while ~10% contain a familial component. The cause of sporadic ALS remains unclear. However, a clear genetic link to point mutations in the cytosolic Cu2+/Zn2+ superoxide dismutase 1 (SOD1) has been shown in a small group of familial ALS (FALS) patients.3Rosen DR Siddique T Patterson D Figlewicz DA Sapp P Hentati A et al.Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.Nature. 1993; 362: 59-62Crossref PubMed Scopus (5568) Google Scholar,4Andersen PM Sims KB Xin WW Kiely R O'Neill G Ravits J et al.Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes.Amyotroph Lateral Scler Other Motor Neuron Disord. 2003; 4: 62-73Crossref PubMed Scopus (248) Google Scholar Both mouse5Gurney ME Pu H Chiu AY Dal Canto MC Polchow CY Alexander DD et al.Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.Science. 1994; 264: 1772-1775Crossref PubMed Scopus (3494) Google Scholar and rat6Howland DS Liu J She Y Goad B Maragakis NJ Kim B et al.Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS).Proc Natl Acad Sci USA. 2002; 99: 1604-1609Crossref PubMed Scopus (705) Google Scholar models that overexpress the G93A, G82R, or G37R mutations have been developed, and these show a similar disease phenotype and progression to the one seen in both familial and sporadic forms of the disease in humans. Degeneration of motor neurons is clearly a complex process and probably involves multiple pathways including formation of protein aggregates, axonal transport defects, oxidative damage, mitochondrial defects, alterations in calcium homeostasis and, finally, cell death.7Julien JP Amyotrophic lateral sclerosis. unfolding the toxicity of the misfolded.Cell. 2001; 104: 581-591Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar,8Rowland LP Shneider NA Amyotrophic lateral sclerosis.N Engl J Med. 2001; 344: 1688-1700Crossref PubMed Scopus (1617) Google Scholar Interestingly, there is mounting evidence that axonal atrophy and withdrawal from the muscle may occur early in the disease process.9Fischer LR Culver DG Tennant P Davis AA Wang M Castellano-Sanchez A et al.Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man.Exp Neurol. 2004; 185: 232-240Crossref PubMed Scopus (1016) Google Scholar Glial cell line–derived neurotrophic factor (GDNF), which has been shown to protect motor neurons in a number of different models,10Henderson CE Phillips HS Pollock RA Davies AM Lemeulle C Armanini M et al.GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle.Science. 1994; 266: 1062-1064Crossref PubMed Scopus (1139) Google Scholar,11Mohajeri MH Figlewicz DA Bohn MC Intramuscular grafts of myoblasts genetically modified to secrete glial cell line-derived neurotrophic factor prevent motoneuron loss and disease progression in a mouse model of familial amyotrophic lateral sclerosis.Hum Gene Ther. 1999; 10: 1853-1866Crossref PubMed Scopus (126) Google Scholar,12Acsadi G Anguelov RA Yang H Toth G Thomas R Jani A et al.Increased survival and function of SOD1 mice after glial cell-derived neurotrophic factor gene therapy.Hum Gene Ther. 2002; 13: 1047-1059Crossref PubMed Scopus (150) Google Scholar,13Wang CY Yang F He XP Je HS Zhou JZ Eckermann K et al.Regulation of neuromuscular synapse development by glial cell line-derived neurotrophic factor and neurturin.J Biol Chem. 2002; 277: 10614-10625Crossref PubMed Scopus (68) Google Scholar is present at high levels in embryonic limb and muscle at the time of innervation, and is necessary for normal neuromuscular development.13Wang CY Yang F He XP Je HS Zhou JZ Eckermann K et al.Regulation of neuromuscular synapse development by glial cell line-derived neurotrophic factor and neurturin.J Biol Chem. 2002; 277: 10614-10625Crossref PubMed Scopus (68) Google Scholar,14Keller-Peck CR Feng G Sanes JR Yan Q Lichtman JW Snider WD Glial cell line-derived neurotrophic factor administration in postnatal life results in motor unit enlargement and continuous synaptic remodeling at the neuromuscular junction.J Neurosci. 2001; 21: 6136-6146Crossref PubMed Google Scholar GDNF also increases neural sprouting and prevents cell death.14Keller-Peck CR Feng G Sanes JR Yan Q Lichtman JW Snider WD Glial cell line-derived neurotrophic factor administration in postnatal life results in motor unit enlargement and continuous synaptic remodeling at the neuromuscular junction.J Neurosci. 2001; 21: 6136-6146Crossref PubMed Google Scholar,15Blesch A Tuszynski MH GDNF gene delivery to injured adult CNS motor neurons promotes axonal growth, expression of the trophic neuropeptide CGRP, and cellular protection.J Comp Neurol. 2001; 436: 399-410Crossref PubMed Scopus (95) Google Scholar,16Deshpande DM Kim YS Martinez T Carmen J Dike S Shats I et al.Recovery from paralysis in adult rats using embryonic stem cells.Ann Neurol. 2006; 60: 32-44Crossref PubMed Scopus (232) Google Scholar Healthy motor neurons express GDNF receptor-α and c-Ret, the heterodimer receptor system of GDNF, and can bind, internalize, and transport the protein in both antero- and retrograde directions in a receptor-dependent manner.17Glazner GW Mu X Springer JE Localization of glial cell line-derived neurotrophic factor receptor alpha and c-ret mRNA in rat central nervous system.J Comp Neurol. 1998; 391: 42-49Crossref PubMed Scopus (102) Google Scholar,18Leitner ML Molliver DC Osborne PA Vejsada R Golden JP Lampe PA et al.Analysis of the retrograde transport of glial cell line-derived neurotrophic factor (GDNF), neurturin, and persephin suggests that in vivo signaling for the GDNF family is GFRalpha coreceptor-specific.J Neurosci. 1999; 19: 9322-9331PubMed Google Scholar,19von Bartheld CS Wang X Butowt R Anterograde axonal transport, transcytosis, and recycling of neurotrophic factors: the concept of trophic currencies in neural networks.Mol Neurobiol. 2001; 24: 1-28Crossref PubMed Google Scholar In transgenic mice overexpressing GDNF in muscle, a hyperinnervation of muscle by motor neurons has been reported.20Nguyen QT Parsadanian AS Snider WD Lichtman JW Hyperinnervation of neuromuscular junctions caused by GDNF overexpression in muscle.Science. 1998; 279: 1725-1729Crossref PubMed Scopus (228) Google Scholar However, delivery of GDNF to either motor neurons in the spinal cord or muscle end plates in adult animals is difficult because of poor penetration of this factor from the blood into body tissues. Recent studies have used gene therapy approaches to deliver GDNF and other growth factors directly to the muscle in a mouse model of FALS, with encouraging results.11Mohajeri MH Figlewicz DA Bohn MC Intramuscular grafts of myoblasts genetically modified to secrete glial cell line-derived neurotrophic factor prevent motoneuron loss and disease progression in a mouse model of familial amyotrophic lateral sclerosis.Hum Gene Ther. 1999; 10: 1853-1866Crossref PubMed Scopus (126) Google Scholar,21Kaspar BK Llado J Sherkat N Rothstein JD Gage FH Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model.Science. 2003; 301: 839-842Crossref PubMed Scopus (750) Google Scholar However, there may be difficultly in translating these studies to larger species such as rat and monkey. Disease progression in ALS is associated with loss of motor neurons, leading to muscle atrophy and eventually to respiratory failure and death. In an attempt to prevent muscle atrophy and death of spinal motor neurons, an ex vivo gene therapy that targets skeletal muscles may be effective. The efficacy of this idea has successfully been proven by a study report showing that GDNF delivery to muscle using genetically modified myoblasts can produce protective effects on motor neurons in the spinal cord.11Mohajeri MH Figlewicz DA Bohn MC Intramuscular grafts of myoblasts genetically modified to secrete glial cell line-derived neurotrophic factor prevent motoneuron loss and disease progression in a mouse model of familial amyotrophic lateral sclerosis.Hum Gene Ther. 1999; 10: 1853-1866Crossref PubMed Scopus (126) Google Scholar However, in clinical trials, it may be difficult to amplify cell numbers by passaging to obtain cell numbers sufficient for biological significance after injection back into the muscle.22Cossu G Mavilio F Myogenic stem cells for the therapy of primary myopathies: wishful thinking or therapeutic perspective.J Clin Invest. 2000; 105: 1669-1674Crossref PubMed Scopus (135) Google Scholar Human mesenchymal stem cells (hMSCs) are found in bone marrow as well as in other mesenchymal tissues. They are easy to harvest and can be expanded ex vivo to clinically relevant numbers while retaining their normal karyotype and differentiation capacity.23Prockop DJ Marrow stromal cells as stem cells for nonhematopoietic tissues.Science. 1997; 276: 71-74Crossref PubMed Scopus (4157) Google Scholar,24Pittenger MF Mackay AM Beck SC Jaiswal RK Douglas R Mosca JD et al.Multilineage potential of adult human mesenchymal stem cells.Science. 1999; 284: 143-147Crossref PubMed Scopus (18139) Google Scholar,25Deans RJ Moseley AB Mesenchymal stem cells: biology and potential clinical uses.Exp Hematol. 2000; 28: 875-884Abstract Full Text Full Text PDF PubMed Scopus (1319) Google Scholar They appear to have a significant effect on disease progression in a number of animal models of human disease, including heart damage, stroke, and Parkinson's disease. While the mechanisms of action of this protective effect remain to be elucidated, they may include growth factor release or increased angiogenesis.26Picinich SC Mishra PJ Mishra PJ Glod J Banerjee D The therapeutic potential of mesenchymal stem cells. Cell- & tissue-based therapy.Expert Opin Biol Ther. 2007; 7: 965-973Crossref PubMed Scopus (128) Google Scholar In this study we show that combining the specific administration of GDNF with the therapeutic effects of hMSC transplants leads to a significant improvement in both survival and functioning of motor neurons in a well established rat model of FALS. It therefore represents a unique, targeted, and practical therapeutic approach to this devastating disease. hMSCs were isolated from neonatal bone marrow aspirates from healthy donors after obtaining informed consent, and confirmed by immunophenotyping and multilineage differentiation.27Campagnoli C Bellantuono I Kumar S Fairbairn LJ Roberts I Fisk NM High transduction efficiency of circulating first trimester fetal mesenchymal stem cells: potential targets for in utero ex vivo gene therapy.BJOG. 2002; 109: 952-954Crossref PubMed Scopus (26) Google Scholar,28Baxter MA Wynn RF Jowitt SN Wraith JE Fairbairn LJ Bellantuono I Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion.Stem Cells. 2004; 22: 675-682Crossref PubMed Scopus (641) Google Scholar,29Wynn RF Hart CA Corradi-Perini C O'Neill L Evans CA Wraith JE et al.A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow.Blood. 2004; 104: 2643-2645Crossref PubMed Scopus (644) Google Scholar This line was then genetically modified to express green fluorescent protein (GFP) using retrovirus (hMSCGFP).27Campagnoli C Bellantuono I Kumar S Fairbairn LJ Roberts I Fisk NM High transduction efficiency of circulating first trimester fetal mesenchymal stem cells: potential targets for in utero ex vivo gene therapy.BJOG. 2002; 109: 952-954Crossref PubMed Scopus (26) Google Scholar hMSCGFP were infected with a lentiviral construct encoding GDNF under the control of phosphoglycerol kinase promoter (Figure 1a). GDNF protein was detected by enzyme-linked immunosorbent assay in the conditioned medium and shown to be released at a rate of 480 pg/24 hours/million cells (Figure 1b). Noninfected hMSCGFP did not release detectable amounts of GDNF. Immunocytochemical analysis using hMSCGFP-GDNF titer showed that ~98 and ~95% of total cells expressed GFP and GDNF protein, respectively (Figure 1c). We next addressed the question of whether hMSCGFP-GDNF could be transplanted into the skeletal muscle of presymptomatic ALS rats (SOD1G93A rats). However we found that, after direct implantation into intact muscle, there was very poor survival and integration of the cells (data not shown). It has previously been demonstrated that hMSCs can integrate into the skeletal muscle in nude mice but require focal muscle injury using cardiotoxin prior to transplantation in order to survive.30De BC Dell'Accio F Vandenabeele F Vermeesch JR Raymackers JM Luyten FP Skeletal muscle repair by adult human mesenchymal stem cells from synovial membrane.J Cell Biol. 2003; 160: 909-918Crossref PubMed Scopus (381) Google Scholar The injury appears to create a better environment for cell survival and integration, perhaps through the release of cytokines and other growth factors. In this study we used intramuscular injection of a local anesthetic, bupivacaine hydrochloride (BVC), to induce focal injury prior to transplantation.31Steer JH Mastaglia FL Papadimitriou JM Van Bruggen I Bupivacaine-induced muscle injury. The role of extracellular calcium.J Neurol Sci. 1986; 73: 205-217Abstract Full Text PDF PubMed Scopus (24) Google Scholar,32Hill M Wernig A Goldspink G Muscle satellite (stem) cell activation during local tissue injury and repair.J Anat. 2003; 203: 89-99Crossref PubMed Scopus (217) Google Scholar Female SOD1G93A rats (80 days, presymptomatic) were immunosuppressed with cyclosporine, and then BVC was bilaterally injected into the tibialis anterior (TA) muscle (Supplementary Figure S1). Twenty-four hours, 1 and 2 weeks later hMSCGFP-GDNF (120,000 cells in 30 µl) were injected into the same muscle. All the animals were observed until their respective end points, defined as the inability to right themselves after 30 seconds. We first checked whether hMSCs could survive transplantation in the muscle of SOD1G93A rats having prior toxin lesions. Even at the end point of the disease, using immunostaining with anti-GFP antibody (Figure 2a and b) and GFP expression (Figure 2c) many grafted cells could be detected within the muscle. There were no adverse effects in any of the animals and no sign of tumor formation. Immunostaining for laminin antibody to identify the basal lamina (Figure 2d) revealed that GFP-positive hMSCs resided both within and between the laminin-positive basal lamina and muscle fibers (designated by arrows and arrow head in Figure 2d). The GFP signal did not extend to the sarcolemma of the adjacent myofibers, thereby indicating that the cells had not fused with rat muscle fibers. Double staining with the human specific marker (human nuclei) and GFP also showed the presence of surviving hMSCs in the muscles (Figure 2e). Additionally, our preliminary data showed that hMSCs could survive in the muscles even after a single transplantation after 24 hours of BVC injection. However, the number of surviving cells was higher with more injections (data not shown). We also performed reverse transcriptase PCR on muscle tissues, using primers specific for human or rat cDNA. At 2 days and 8 weeks after transplantation, we detected human β-actin in the TA muscles that had been injected with hMSCGFP-GDNF (Figure 2f), whereas these mRNAs were not detected in TA muscle that had received no transplant. Further, the expression of human myosin heavy chain IIx/d (MyHC-IIx/d) gene was also detected and shown to be increased in the transplanted muscles, thereby suggesting that some of the hMSCs transplanted in the muscles may have acquired the skeletal muscle phenotype. In order to establish whether GDNF was being released by the hMSCs, TA muscles from transplanted or control animals were dissected and then processed for immunohistochemistry using GFP and GDNF antibody (Figure 2g). Significant amounts of GDNF could be detected in the areas with hMSCGFP, particularly between the basal lamina and muscle fibers (Figure 2g). We also confirmed visual expression of GDNF with protein expression, using enzyme-linked immunosorbent assay which showed that hMSCGFP-GDNF released significant amounts of this growth factor into the skeletal muscle (Figure 2h). Together these data show that adult human mesenchymal cells can survive well within rat muscle tissues and can release GDNF, provided a minor toxic lesion is present. We next analyzed neuromuscular junctions (NMJs) within the region of the transplant in order to establish whether the GDNF had any effect on end-plate innervation. For these studies, another cohort of 80-day-old female SOD1G93A rats (n = 13) were unilaterally injected with BVC in their TA muscles and, after 24 hours, 1 week, and 2 weeks, transplanted with hMSCGFP-GDNF (n = 5), hMSCGFP (n = 4), or just vehicle infusions (control; n = 4). The level of innervation in the transplanted muscles was estimated using double staining for axons and motor end plates, based on the levels of acetylcholine receptor postsynaptic clusters (Figure 3a–c). We have previously shown that, while >80% of end plates were innervated in the presymptomatic SOD1G93A rats up to 80 days of age, this number gradually decreased to the point where all end plates were denervated by the end stage.33Suzuki M McHugh J Tork C Shelley B Klein SM Aebischer P et al.GDNF secreting human neural progenitor cells protect dying motor neurons, but not their projection to muscle, in a rat model of familial ALS.PLoS ONE. 2007; 2: e689Crossref PubMed Scopus (251) Google Scholar In this study, ~75% of the end plates were denervated in the muscle of nontransplanted control SOD1G93A rats at 122 days old (Figure 3e and f). The number of denervated end plates tended to be reduced in hMSCGFP transplanted rats, although this difference did not reach statistical significance (Figure 3e and f). However, there was a significant decrease in end-plate denervation within the hMSCGFP-GDNF group when compared with the nongrafted control (Figure 3e and f; P < 0.05). The localization of acetylcholine receptor clusters at the end plate requires the expression of agrin, a large proteoglycan in the synaptic cleft that plays an important role in the maintenance of the molecular architecture of the postsynaptic membrane.34McConville J Vincent A Diseases of the neuromuscular junction.Curr Opin Pharmacol. 2002; 2: 296-301Crossref PubMed Scopus (26) Google Scholar An earlier report showed that agrin expression was significantly reduced in the skeletal muscles of symptomatic SOD1G93A mice.35Dobrowolny G Giacinti C Pelosi L Nicoletti C Winn N Barberi L et al.Muscle expression of a local Igf-1 isoform protects motor neurons in an ALS mouse model.J Cell Biol. 2005; 168: 193-199Crossref PubMed Scopus (281) Google Scholar The number of agrin-positive end plates was reduced in nontransplanted SOD1G93A rats (23.1 ± 4.8%/total end plates) as compared to hMSCGFP (46.6 ± 15.8%) or hMSCGFP-GDNF (55.6 ± 18.3%) animals (Figure 3d), further underscoring a role for hMSCGFP-GDNF in the maintenance of muscle innervation. In order to establish whether hMSCGFP-GDNF could ameliorate motor neuron loss, we next counted Nissl-stained or choline acetyltransferase–positive cells within the specific lumbar spinal cord region (L2–4) that had projections into the transplanted hindlimb muscles. We had previously confirmed that the TA muscle transplanted with hMSCs did receive projections from the spinal cord region analyzed.33Suzuki M McHugh J Tork C Shelley B Klein SM Aebischer P et al.GDNF secreting human neural progenitor cells protect dying motor neurons, but not their projection to muscle, in a rat model of familial ALS.PLoS ONE. 2007; 2: e689Crossref PubMed Scopus (251) Google Scholar While there was a significant loss of choline acetyltransferase-positive motor neurons in nontransplanted SOD1G93A rats (Figure 4a, c and e), this loss was prevented by transplants of either hMSCGFP or hMSCGFP-GDNF (Figure 4g). However, the level of protection afforded by the hMSCGFP-GDNF group was larger (P < 0.01 versus control) as compared to the hMSCGFP group (P < 0.05 versus control). Interestingly, the hMSCGFP-GDNF appeared to specifically protect the larger motor neuron pool, or increase the size of smaller surviving motor neurons, as observed from detailed cell counting combined with size measurements (Figure 4h). Activation of host glial cells is one hallmark of ALS, and increases with disease progression in the SOD1G93A rats. This may be protective or may contribute to motor neuron death. Significant astrogliosis was detected in the ventral horn of the lumbar spinal cord in nontransplanted SOD1G93A rats (Supplementary Figure S2). The numbers of host glial fibrillary acidic protein (GFAP) reactive astrocytes tended to be reduced in both hMSCGFP- and hMSCGFP-GDNF transplanted rats at 6 weeks after transplantation, although the difference did not reach statistical significance. This suggests that the protective effects of hMSCGFP-GDNF were not mediated entirely through modulation of host reactive astrogliosis. We also determined the levels of microglial activation, using immunostaining for microglial marker OX-42 (CD11b). As seen for GFAP staining, there was no obvious difference in the levels of microglial activation in the lumbar spinal cord regions that connected to the transplanted hindlimb muscles, although the sizes and branching of many microglia were smaller in the animals that had received transplants (Supplementary Figure S2). We next wanted to establish whether intramuscular hMSCGFP-GDNF transplantation could prolong the survival period in SOD1G93A rats. First, we showed that partial muscle injury with BVC at 80 days of age did not change disease onset and progression compared with nontreated (i.e., nonpartial injury using BVC) control SOD1G93A rats (data not shown). The efficacy of intramuscular transplantation was then tested using GDNF-secreting hMSCs in a new cohort of SOD1G93A rats. For these studies, we used two different cohorts of rats, and the variation with regard to disease onset and progression in our SOD1G93A rats was observed as previously described.36Suzuki M Tork C Shelley B McHugh J Wallace K Klein SM et al.Sexual dimorphism in disease onset and progression of a rat model of ALS.Amyotroph Lateral Scler. 2007; 8: 20-25Crossref PubMed Scopus (49) Google Scholar In a third cohort of SOD1G93A rats with early disease progression (n = 9), hMSCGFP-GDNF were bilaterally transplanted into the TA, forelimb triceps brachii, and the long muscles of the dorsal trunk (Supplementary Figure S1). The survival period in the hMSCGFP-GDNF transplanted rats was significantly prolonged by 18 days (P < 0.05; Figure 5a and b) as compared to the control SOD1G93A littermates (n = 9). We next addressed the question of whether this effect would be reproducible in another colony of our SOD1G93A rats with slow disease progression,36Suzuki M Tork C Shelley B McHugh J Wallace K Klein SM et al.Sexual dimorphism in disease onset and progression of a rat model of ALS.Amyotroph Lateral Scler. 2007; 8: 20-25Crossref PubMed Scopus (49) Google Scholar so that we could further dissociate the effects of GDNF release from the effects of the cells themselves. A cohort of female SOD1G93A rats in a colony showing slow disease progression were transplanted at 80 days with either hMSCGFP (n = 13), hMSCGFP-GDNF (n = 14) or BVC-lesioned control cells (n = 14). There was no difference in disease onset in either the hMSCGFP or hMSCGFP-GDNF groups as compared to the control group (Figure 5c). However, hMSCGFP-GDNF transplantation significantly prolonged survival in the SOD1G93A animals by slowing disease progression relative to lesioned control animals (P < 0.05). Although hMSCGFP-transplanted animals showed a delay in progression when compared with control animals, this delay did not reach statistical significance (P = 0.08; Figure 5d and e). The survival period in the hMSCGFP-GDNF transplanted rats was significantly prolonged by ~28 days compared to the control SOD1G93A littermates (Figure 5e). This is one of the biggest effects on survival noted for this rat model of FALS. We also tested limb function using the Basso-Beatti-Bresnahan (BBB) locomotor–rating test. Motor dysfunction progressed at a significantly slower rate in both hMSCGFP and hMSCGFP-GDNF transplanted rats when compared with the control rats (P < 0.05; Figure 5f). In this study we used hMSCs as long-term “mini pumps” to deliver GDNF directly into the skeletal muscles of SOD1G93A rats. The major advantage of using this ex vivo gene therapy approach (cellular delivery of growth factor), rather than direct in vivo gene therapy (force host cells to express growth factor through direct viral injection) is that it is the new cells that provide the growth factor rather than host muscle cells that are undergoing degeneration caused by the disease process.37Aebischer P Kato AC Playng defense against Lou Gehrig's disease.Sci Am. 2007; 297: 86-93Crossref PubMed Scopus (8) Google Scholar,38Suzuki M Svendsen CN Combining growth factor and stem cell therapy for amyotrophic lateral sclerosis.Trends Neurosci. 2008; 31: 192-198Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar Further, it is clear that hMSCs have other poorly characterized effects on the local environment through release of growth factors, reduction in acute inflammation, or enhancement of angiogenesis.26Picinich SC Mishra PJ Mishra PJ Glod J Banerjee D The therapeutic potential of mesenchymal stem cells. Cell- & tissue-based therapy.Expert Opin Biol Ther. 2007; 7: 965-973Crossref PubMed Scopus (128) Google Scholar Recent preclinical and clinical studies have demonstrated a number of potential therapeutic applications of hMSCs in various diseases such as myocardial infarction, stroke, and graft-versus-host disease.26Picinich SC Mishra PJ Mishra PJ Glod J Banerjee D The therapeutic potential of mesenchymal stem cells. Cell- & tissue-based therapy.Expert Opin Biol Ther. 2007; 7: 965-973Crossref PubMed Scopus (128) Google Scholar It was of great interest to us that the hMSCs on their own had a strong trend toward increasing motor neuron numbers and improving the functional performance of neurons. However, only when combined with GDNF did this effect reach significant levels. Satellite cells and myoblasts represent the natural first choice in ex vivo therapeutics for skeletal muscle because of their intrinsic myogenic commitment, and have been used earlier with some success for delivering GDNF to the muscle in a mouse model" @default.
• W2070542281 created "2016-06-24" @default.
• W2070542281 creator A5001356149 @default.
• W2070542281 creator A5006078376 @default.
• W2070542281 creator A5040634756 @default.
• W2070542281 creator A5058323604 @default.
• W2070542281 creator A5067326029 @default.
• W2070542281 creator A5076105306 @default.
• W2070542281 creator A5078754682 @default.
• W2070542281 creator A5089072780 @default.
• W2070542281 date "2008-12-01" @default.
• W2070542281 modified "2023-10-03" @default.
• W2070542281 title "Direct Muscle Delivery of GDNF With Human Mesenchymal Stem Cells Improves Motor Neuron Survival and Function in a Rat Model of Familial ALS" @default.
• W2070542281 cites W1488103009 @default.
• W2070542281 cites W1493049774 @default.
• W2070542281 cites W1819718829 @default.
• W2070542281 cites W1844154778 @default.
• W2070542281 cites W1965953554 @default.
• W2070542281 cites W1970981381 @default.
• W2070542281 cites W1976371324 @default.
• W2070542281 cites W1979480555 @default.
• W2070542281 cites W1990509070 @default.
• W2070542281 cites W1994452959 @default.
• W2070542281 cites W1998461585 @default.
• W2070542281 cites W2002104055 @default.
• W2070542281 cites W2007304811 @default.
• W2070542281 cites W2007516825 @default.
• W2070542281 cites W2009883535 @default.
• W2070542281 cites W2013606687 @default.
• W2070542281 cites W2013621644 @default.
• W2070542281 cites W2017286200 @default.
• W2070542281 cites W2020917314 @default.
• W2070542281 cites W2026667906 @default.
• W2070542281 cites W2030723260 @default.
• W2070542281 cites W2035133362 @default.
• W2070542281 cites W2040891140 @default.
• W2070542281 cites W2053365512 @default.
• W2070542281 cites W2068529877 @default.
• W2070542281 cites W2071898079 @default.
• W2070542281 cites W2073864172 @default.
• W2070542281 cites W2083225096 @default.
• W2070542281 cites W2088540455 @default.
• W2070542281 cites W2091526175 @default.
• W2070542281 cites W2092312715 @default.
• W2070542281 cites W2096386031 @default.
• W2070542281 cites W2097066519 @default.
• W2070542281 cites W2101910698 @default.
• W2070542281 cites W2107768418 @default.
• W2070542281 cites W2111016560 @default.
• W2070542281 cites W2116489844 @default.
• W2070542281 cites W2121904811 @default.
• W2070542281 cites W2122082144 @default.
• W2070542281 cites W2124836073 @default.
• W2070542281 cites W2128650326 @default.
• W2070542281 cites W2131017387 @default.
• W2070542281 cites W2141248581 @default.
• W2070542281 cites W2150395635 @default.
• W2070542281 cites W2150994376 @default.
• W2070542281 cites W2154549928 @default.
• W2070542281 cites W2159999899 @default.
• W2070542281 cites W2173520530 @default.
• W2070542281 cites W4236884331 @default.
• W2070542281 cites W69871636 @default.
• W2070542281 doi "https://doi.org/10.1038/mt.2008.197" @default.
• W2070542281 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2678899" @default.
• W2070542281 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/18797452" @default.
• W2070542281 hasPublicationYear "2008" @default.
• W2070542281 type Work @default.
• W2070542281 sameAs 2070542281 @default.
• W2070542281 citedByCount "229" @default.
• W2070542281 countsByYear W20705422812012 @default.
• W2070542281 countsByYear W20705422812013 @default.
• W2070542281 countsByYear W20705422812014 @default.
• W2070542281 countsByYear W20705422812015 @default.
• W2070542281 countsByYear W20705422812016 @default.
• W2070542281 countsByYear W20705422812017 @default.
• W2070542281 countsByYear W20705422812018 @default.
• W2070542281 countsByYear W20705422812019 @default.
• W2070542281 countsByYear W20705422812020 @default.
• W2070542281 countsByYear W20705422812021 @default.
• W2070542281 countsByYear W20705422812022 @default.
• W2070542281 countsByYear W20705422812023 @default.
• W2070542281 crossrefType "journal-article" @default.
• W2070542281 hasAuthorship W2070542281A5001356149 @default.
• W2070542281 hasAuthorship W2070542281A5006078376 @default.
• W2070542281 hasAuthorship W2070542281A5040634756 @default.
• W2070542281 hasAuthorship W2070542281A5058323604 @default.
• W2070542281 hasAuthorship W2070542281A5067326029 @default.
• W2070542281 hasAuthorship W2070542281A5076105306 @default.
• W2070542281 hasAuthorship W2070542281A5078754682 @default.
• W2070542281 hasAuthorship W2070542281A5089072780 @default.
• W2070542281 hasBestOaLocation W20705422811 @default.
• W2070542281 hasConcept C14036430 @default.
• W2070542281 hasConcept C160539049 @default.
• W2070542281 hasConcept C169760540 @default.
• W2070542281 hasConcept C170493617 @default.
• W2070542281 hasConcept C185856081 @default.
• W2070542281 hasConcept C198826908 @default.

• next